Pain of Irritable Bowel Syndrome Traced to the Brain

By John Gever
LOS ANGELES, Jan. 9 -- The source of the pain of irritable bowel syndrome may be abnormal brainstem function, researchers here said.
Patients with irritable bowel syndrome showed heightened activity in brain areas responsible for pain sensation and emotional arousal when they anticipated abdominal pain from certain stimuli, even though patients knew the stimuli were not dangerous, reported Steven Berman, M.D., of UCLA, and colleagues, in the Jan. 9 issue of the Journal of Neuroscience.
Anxiety about irritable bowel symptoms is itself one of the condition's most important symptoms, said Dr. Berman and colleagues said, noting that it can exacerbate the severity of physical symptoms, including pain. Altered neurological preparation for expected pain is one explanation for this effect, which is what they set out to explore in their study.
The investigators studied 14 women with irritable bowel syndrome and 12 healthy women. Participants underwent a balloon-driven rectal distention procedure that causes no tissue damage but creates sensations of pressure. The procedure included a light-based visual cue to signal the start. Distentions of 25 and 45 mm Hg were induced, as was a sham distention of 5 mm Hg.
Questionnaires administered just prior to the procedure confirmed that the irritable bowel syndrome patients were more anxious, angry, and stressful beforehand than the healthy individuals. The patients had mean scores of 6.0 for stress, 6.0 for anxiety, and 5.8 for anger at baseline. Corresponding values for controls were 3.2 (P<0.0001), 2.5 (P<0.0001) and 2.4 (P=0.0002).
During the procedure, activity in participants' insula, amygdala, and brainstem was monitored with functional MRI.
Among the most notable findings was the response to the visual cue. The healthy controls showed widespread decreases in brain activity. Dr. Berman and colleagues interpreted this reaction as downregulation of pain-signaling systems, which is a normal response to anticipation of unpleasant sensations consciously understood as innocuous or inescapable.
In contrast, no such decrease in brain activity was seen in the irritable bowel syndrome patients. This indicates that the patients "are more anxious and less able than healthy controls to downregulate activity" associated with anticipated pain, especially in the dorsal brainstem where much of this regulation is centered.
Patients with irritable bowel syndrome also showed stronger brain reactions to the actual rectal distention, relative to controls. At 45 mm Hg, for example, activity cluster scores in the anterior insula among patients were 620 on the left side and 540 on the right. Among controls, the corresponding values were 264 and 279.
A similar pattern occurred with the smaller distentions, but the differences were less pronounced and affected fewer brain areas. In the sham distention, none of the differences reached statistical significance.
On the basis of their findings, Dr. Berman and colleagues concluded that noradrenergic regulation in the brainstem is disrupted in irritable bowel syndrome, although they said more studies are needed to confirm the mechanism.
"Additional research may reveal that some pain patients have a primary difference in their brain's reaction to pain," said Emeran A. Mayer, M.D., another UCLA researcher who worked on the study. "If we can identify receptors and genes associated with these abnormal brain responses, we should improve both identification of predisposed patients and development of effective remedies."
The findings may also have implications for the underlying pathology and possible treatments for fibromyalgia and other chronic pain syndromes.
An estimated 10% to 15% of the adult population in the U.S. has irritable bowel syndrome, about three-quarters female.
Funding for the study was provided by the National Institutes of Health and Novartis Pharmaceuticals.
Dr. Mayer has received research grants from Novartis and has previously served as a consultant.
Primary source: Journal of NeuroscienceSource reference:Berman S, "Reduced brainstem inhibition during anticipated pelvic visceral pain correlates with enhanced brain response to the visceral stimulus in women with irritable bowel syndrome" J Neuroscience 2008; 28: 349-59.

China halts production of Novartis drug

Fri Jun 8, 11:09 AM ET
China's drug watchdog on Friday ordered domestic companies to stop producing and selling Novartis AG's Zelnorm for irritable bowel syndrome and warned patients to stop taking it.
"The risks of Zelnorm outweigh the possible benefits for some patients based on analyses from home and abroad," China's State Food and Drug Administration said in a statement posted to agency's Web site.
The agency said China's National Center for Adverse Drug Reaction Monitoring has received 98 reports of adverse reactions concerning Zelnorm since it was introduced to the Chinese market in 2003. Most involved diarrhea and nausea, with one reported case of abnormally fast heartbeat and another of low blood pressure.
Two drug companies in southern city of Chongqing and one Beijing drug manufacturer were ordered to stop production of the drug, the agency said. A third company in Chongqing was told to halt plans to start producing it.
The official Xinhua News Agency said that hundreds of thousands of Chinese patients use the drug.
"We have announced this morning that we are complying with a request from the local authority to suspend the marketing and sales activity of (Zelnorm) in China," Novartis spokeswoman Corinne Hoff said.
"More than 85 percent of our sales were in the U.S," she said.
"I cannot give you the sales figures for China, but it's not significant," Hoff said.
Novartis agreed in March to stop selling Zelnorm in the United States, the name under which it was sold there, at the request of the Food and Drug Administration after it was linked to a higher chance of heart attack, stroke and worsening chest pain that can become a heart attack.

Studies Lead to Withdrawal of Drug for Bowel Ailment

By GARDINER HARRIS
WASHINGTON, March 30 — The maker of Zelnorm, a medicine that treats constipation-related irritable bowel syndrome, stopped selling the drug Friday after federal drug officials concluded that it might cause heart attacks and strokes.
In 29 studies, 13 of 11,614 patients given Zelnorm had heart problems, including one who died. Just one of 7,031 patients given placebos had similar problems.
Officials at the Food and Drug Administration said the drug was not effective enough to merit such risks.
Executives at the drug’s maker, Novartis, the giant Swiss drug concern, said the studies’ findings could be a fluke and vowed to continue selling Zelnorm in Europe.
Driven by aggressive advertising, Zelnorm had $561 million in sales last year, up 34 percent from 2005. About 500,000 people are currently taking the medicine for the ailment, which is also known as I.B.S.
Patients criticized the food and drug agency’s decision.
“I can’t believe the F.D.A. would do such a thing. Why are they being so cruel?” asked Lori Egan, 39, of Fredericksburg, Va. “I would rather take my chances of having a heart attack than live in I.B.S. hell.”